Hepatic peroxisome proliferator-activated receptor alpha mediates the major metabolic effects of Wy-14643

Background and AimPeroxisome proliferator-activated receptor alpha (PPAR) is a molecular target of various fibrate drugs clinically used to lower serum lipids. However, the tissue-specific functions of PPAR remain to be elucidated. This study aimed to explore the tissue-specific functions of PPAR in response to Wy-14643. MethodsA hepatocyte-specific Ppara knockout mouse line was used to explore the impact of hepatic PPAR activity on the systemic response to treatment with the potent PPAR agonist Wy-14643. ResultsWy-14643 mainly activated hepatic PPAR and regulated the expression of PPAR target genes in liver. Hepatic Ppara disruption abolished the triglyceride lowering effects of Wy-14643, prevented agonist-induced hypophagia, and ablated PPAR target gene response in the liver. ConclusionsThese findings indicate that Wy-14643 treatment mainly activates hepatic PPAR, and the hypolipidemic and hypophagic effects of Wy-14643 are dependent on PPAR activation within hepatocytes.